Successful treatment of addictive disorders depends not only on obtaining, but also on maintaining abstinence, and therefore preventing relapse is an essential therapeutic approach. Relapse is often triggered by environmental cues that signal availability of the drug, inducing the retrieval of drug-associated memories. Disrupting cue-induced memories is a new strategy for reducing relapse risk and can be accomplished via one of two approaches: (1) by preventing reconsolidation of a reactivated memory or (2) by extinction of the memory. When a memory is retrieved it enters a labile state and protein synthesis-dependent restabilization (reconsolidation) is necessary for the long-term maintenance of the memory. To prevent reconsolidation, drug- related cues are briefly presented followed by an intervention designed to inhibit the re-storage of the memory, thus reducing the ability of the memory to invoke craving and relapse in the future. Alternatively, when drug- associated cues are repeatedly presented in the absence of the drug, the individual learns that the cues are no longer predictive of drug availability, leading to less craving, and a subsequent inhibition of drug-seeking behavior. This learning process is called memory extinction. Although extinction and reconsolidation involve some of the same neurobiological processes, there may be components of the two pathways that diverge, allowing the development of a single medication that simultaneously enhances extinction and inhibits reconsolidation. A major limitation in previously tested medications has been the unintentional strengthening of the drug-associated memory by reconsolidation rather than extinction enhancement. However, a treatment strategy that concurrently alters extinction and reconsolidation would solve this problem. Drugs of abuse alter excitatory signaling within the basolateral amygdala (BLA) and other memory centers of the brain, leading to biochemical and structural synaptic changes that result in pathologically strengthened memories. This proposal will use a rat model of addiction to study the mechanistic and functional role of calcium/calmodulin dependent protein kinase II alpha (CaMKIIa), a protein activated by the influx of calcium through N-methyl-D-aspartate (NMDA) receptors, following cocaine-associated memory extinction and reconsolidation and to validate it as a target for relapse prevention. CaMKIIa activation leads to its autophosphorylation and translocation to dendritic spines, as well as phosphorylation of synaptic targets including glutamatergic receptors and related structural proteins. CaMKII has been implicated in a number of memory paradigms, but its specific role following drug- associated memory extinction and reconsolidation has been poorly studied. The proposed studies will test the hypothesis that differential activation of CaMKII in th BLA following cocaine-associated memory manipulations alters the phosphorylation patterns of synaptic proteins, subsequently impacting dendritic spine morphology and cocaine-seeking behavior. The proposal will evaluate the potential of a manipulation of CaMKII or a downstream signaling molecule as a potential pharmacological treatment for the prevention of relapse.